JP2017520275A - Use of anti-aging glycopeptides to enhance pancreatic cell health, survival, and improve transplant outcomes - Google Patents

Abstract

The present disclosure provides an in vitro method for enhancing the engraftment of isolated pancreatic cells, wherein the isolated pancreatic cells are subjected to gem-difluorination of general formula (I) prior to transplantation in a subject in need thereof. Contacting a C-glycopeptide compound or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I. [Selection] Figure 2

Description

[Cross-reference of related applications]
[0001] This application claims priority from US Provisional Application No. 62 / 007,626, filed June 4, 2014, the specification of which is incorporated herein by reference.

(A) Field
[0002] The disclosed subject matter relates generally to the use of anti-aging glycopeptides. More particularly, the subject matter relates to the use of anti-aging glycopeptides that enhance human pancreatic cell engraftment.

(B) Related prior art
[0003] Antifreeze biological compounds, particularly glycoproteins, exist in the natural environment. These compounds are present, for example, in some fish, and some fish can survive in low temperature environments (ie, near 0 degrees or below freezing) with these compounds. Scientists have been studying how antifreeze compounds from the natural environment (fish, amphibians, plants, insects, etc.) affect these phenomena. Research has been focused on the synthesis of similar compounds that are sufficiently stable and for commercial use that their activity is at least equal to or greater than that of the natural molecule.

  [0004] With antifreeze protein (AFP), there is increasing interest in the ability of antifreeze proteins to protect cells under a variety of conditions. Antifreeze proteins are found naturally in Arctic and Antarctic fish and other invertebrates living in cold climates and are responsible for maintaining cells and tissues to function at sub-freezing temperatures. AFP was successfully isolated in the 1950s and has demonstrated the ability to reduce body fluid freezing temperatures in a non-uniform manner by binding to ice crystals.

  [0005] Initial experiments with these compounds in the field of organ and tissue transplantation have shown promising results, so that these compounds can be removed from harmful conditions associated with the recovery-storage-reperfusion process. It became an attractive treatment candidate to protect cells. In addition, during cryopreservation of various cells, including islets of Langerhans, the additional advantage of significantly increasing cell viability and function when supplemented with AFP during cryostasis has been demonstrated. . The anti-aging glycopeptide (AAGP ™) used in the present invention is derived from an attempt to obtain an analog of an antifreeze glycoprotein.

[0006] Anti-aging glycopeptide (AAGP ™) compounds are applied under severe cellular stress such as nutrient deficiency, high and low temperature storage, oxidative stress by hydrogen peroxide (H ₂ O ₂ ), UV irradiation and inflammation A gem difluorinated C-glycopeptide that has been proposed to have potential.

  [0007] Beta cell transplantation is the transplantation of isolated beta islet cells from a donor pancreas into another human. Beta cell transplantation is an experimental treatment for type 1 diabetes. When transplanted, islet β cells begin to produce insulin and actively regulate glucose levels in the blood. Although significant progress has been made in the field of islet transplantation, there are still many obstacles that hinder the widespread application of islet transplantation. Two of the most important limitations are the current lack of means to prevent islet rejection and the limited supply of beta islet cells for transplantation. Current immunosuppressive regimens can prevent beta islet cell failure for months to years, but the drugs used in these treatments are expensive and may increase the risk of certain malignancies and opportunistic infections . In addition, although somewhat ironic, the most commonly used drugs [daclizumab (Zenapax ™), sirolimus (Rapamune ™) and tacrolimus (Prograf) ( Trademark))] is also known to impair normal β islet cell function and / or insulin action.

  [0008] The long-term outcome of islet transplantation has improved significantly at highly specialized central centers, with a 5-year insulin-independent rate exceeding 50%. In order to balance it, it is necessary to re-introduce insulin therapy at a late point. Many factors contribute to substantial graft loss, particularly in the early stages after intraportal infusion, and inadequate islet mass can limit a patient's permanent glycemic control. One factor leading to acute graft loss is hypoxia, and many islets die immediately after transplantation and before full angiogenesis is restored. Other reasons for graft loss include immediate blood-mediated inflammatory response, alloimmunity, autoimmune recurrence and chronic exposure to diabetes-induced immunosuppressive drugs. These factors account for about 60% of immediate and early islet loss, resulting in insufficient islet mass to maintain a functional transplant.

  [0009] Based on this evidence, much attention is currently focused on the potential of AFP and the use of AFP in health science, especially in the field of transplantation. However, data reflecting the potential impact of islet transplantation is lacking, and large initial graft loss seems to be unavoidable in islet transplantation. The cytoprotective effect of this AAGP ™ compound was tested in isolated human islets maintained in ambient temperature culture conditions, exposed to toxins and transplanted into an immunodeficient mouse model as an indicator of preservation of initial islet mass.

  [0010] Accordingly, there is a need for methods to improve the supply of isolated islet cells.

  [0011] There is a need for methods to improve the health and survival of isolated cells.

［式中、
Ｎは、１〜５の整数であり、
Ｒ^４ ＝ Ｈ、ＡＡ_１又はＡＡ_１−ＡＡ_２であり、
Ｒ^５ ＝ ＯＨ、ＡＡ_１又はＡＡ_１−ＡＡ_２であり、
ＡＡ_１及びＡＡ_２は、独立して、非極性側鎖を有するアミノ酸を表し、
Ｒ^１、Ｒ^２、Ｒ^３は、独立した基であり、ここで、Ｒ^１、Ｒ^２及びＲ^３のうちの２つは、Ｈ、ＣＨ_３、ＣＨ_２Ｐｈ、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ（ＣＨ_３）_２又はＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_３から選択され、Ｒ^１、Ｒ^２、Ｒ^３のうちの残りは、

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−グリコシド基又はＣＨ_２−ＯＧＰであり、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^１ ＝ Ｒ^２ ＝ Ｈ、ＣＨ_３、ＣＨ_２Ｐｈ、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ（ＣＨ_３）_２又はＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_３である場合、
Ｒ^３ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−グリコシド基又はＣＨ_２−ＯＧＰであり、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^１ ＝ Ｒ^３ ＝ Ｈ、ＣＨ_３、ＣＨ_２Ｐｈ、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ（ＣＨ_３）_２又はＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_３である場合、
Ｒ^２ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−グリコシド基又はＣＨ_２−ＯＧＰであり、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^２ ＝ Ｒ^３ ＝ Ｈ、ＣＨ_３、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ（ＣＨ_３）_２又はＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_３である場合、
Ｒ^１ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−グリコシド基又はＣＨ_２−ＯＧＰであり、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］である］
のｇｅｍ−ジフルオロ化Ｃ−グリコペプチド化合物、又は一般式Ｉの化合物の薬学的に許容される、塩基、酸付加塩、水和物若しくは溶媒和物と接触させるステップを含む方法が提供される。 [0012] According to one embodiment, an in vitro method for enhancing engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells or both, comprising:
a) Prior to transplantation in a subject in need of transplantation, the isolated pancreatic cells, isolated pancreatic progenitor cells or both may be represented by the general formula I:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound, or a compound of general formula I.

[0013] According to another embodiment, an in vitro method for improving the insulin secretion function of isolated pancreatic beta cells prior to transplantation in a subject in need thereof, comprising:
a) An isolated pancreatic beta cell is obtained from a gem-difluorinated C-glycopeptide compound of general formula I or a pharmaceutically acceptable base, acid addition salt, hydrate of a compound of general formula I as described above Alternatively, a method is provided that comprises contacting with a solvate.

[0014] According to another embodiment, there is an in vitro method for protecting isolated pancreatic cells, isolated pancreatic progenitor cells or both from immunosuppressive drug toxicity prior to transplantation in a subject in need thereof. And
a) an isolated pancreatic cell, an isolated pancreatic progenitor cell or both of a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base of a compound of general formula I as described above, A method is provided that comprises contacting with an acid addition salt, hydrate or solvate.

[0015] According to another embodiment, an in vitro method for reducing the inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof, comprising:
a) an isolated pancreatic cell, an isolated pancreatic progenitor cell or both of a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base of a compound of general formula I as described above, A method is provided that comprises contacting with an acid addition salt, hydrate or solvate.

[0016] According to another embodiment, a method of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells or both into a subject in need of transplantation comprising:
a) an isolated pancreatic cell, an isolated pancreatic progenitor cell or both of a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base of a compound of general formula I as described above, Contacting with an acid addition salt, hydrate or solvate;
b) transplanting the treated isolated pancreatic cells of step a) into said subject in need of transplantation.

  [0017] The method may further comprise the step a ') prior to step a), ie a') isolating pancreatic cells, pancreatic progenitor cells or both. The method may further comprise contacting the isolated pancreatic cells, isolated pancreatic progenitor cells or both of step b ') step a) prior to step b) with an immunosuppressive drug.

  [0018] In the method of the present invention, the isolated pancreatic cell can be an isolated α cell, isolated β cell, isolated δ cell, isolated γ cell, ε cell, or a combination thereof, Preferably it can be an isolated beta cell.

  [0019] The immunosuppressive drug can be one of daclizumab, sirolimus, tacrolimus, cyclosporine, or combinations thereof.

  [0020] The subject can be a human subject.

  [0021] Isolated pancreatic cells can be isolated from living donors, cadaver donors, or combinations thereof.

［式中、
Ｎは、１〜５の整数であり、
Ｒ^１、Ｒ^２、Ｒ^３は、独立した基であり、ここで、Ｒ^１、Ｒ^２及びＲ^３のうちの２つは、Ｈ、ＣＨ_３から選択され、Ｒ^１、Ｒ^２及びＲ^３のうちの残りは、

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−ＯＧＰから選択され、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’、ＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^１ ＝ Ｒ^２ ＝ Ｈ又はＣＨ_３である場合、
Ｒ^３ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−ＯＧＰから選択され、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’、ＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^１ ＝ Ｒ^３ ＝ Ｈ又はＣＨ_３である場合、
Ｒ^２ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’、ＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、Ｂｎ、トシレート、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ又はＣＨ_２−ＯＧＰから選択され、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^２ ＝ Ｒ^３ ＝ Ｈ又はＣＨ_３である場合、
Ｒ^１ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ又はＣＨ_２−ＯＧＰから選択され、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］である］
の化合物であってもよい。 [0022] In the method of the invention, the compound of formula I is of formula II:

[Where:
N is an integer of 1 to 5,
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are selected from H, CH ₃ and R ¹ , R ² and R ³ The rest of the

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H or CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H or CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″, SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, Bn, tosylate, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H or CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom, or a free alcohol function or a protected alcohol function]]
It may be a compound of

の化合物であってもよい。 [0023] The compound of formula I is of formula III:

It may be a compound of

  [0024] The step of contacting the isolated pancreatic cells comprises from about 0.01 mg / ml to about 5 mg / ml of the compound of Formula I, Formula II or Formula III, or from about 1 mg / ml to about 5 mg / ml of Formula I. And the compound of formula II or formula III.

  [0025] According to another embodiment, isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the methods of the invention are provided.

[0026] According to another embodiment, a method of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells or both into a subject in need of transplantation comprising:
a) A method is provided comprising the step of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the method of the invention into said subject in need of transplantation.

[0027] According to another embodiment, a method of treating diabetes comprising:
a) A method is provided comprising the step of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the method of the invention into said subject in need of transplantation.

  [0028] According to another embodiment, there is provided the use of isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the methods of the invention for transplantation into a subject in need thereof. .

  [0029] According to another embodiment, there is provided the use of isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the methods of the present invention for the treatment of diabetes in a subject in need of transplantation. The

  [0030] According to another embodiment, there are provided isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the methods of the invention for transplantation into a subject in need thereof.

  [0031] According to another embodiment, a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, acid addition salt, water of a compound of general formula I as described above An isolated pancreatic cell, an isolated pancreatic progenitor cell, or both in contact with a solvate or solvate is provided.

  [0032] The compound of general formula I as described above may be a compound of formula II as described above and / or a compound of formula III as described above.

  [0033] The isolated pancreatic cell can be an isolated α cell, isolated β cell, isolated δ cell, isolated γ cell, ε cell, or a combination thereof, and the isolated pancreatic cell is an isolated β cell It is preferable to obtain.

  [0034] The isolated pancreatic cells, isolated pancreatic progenitor cells or both are about 0.01 mg / ml to about 5 mg / ml of the compound of formula I, formula II or formula III, or about 1 mg / ml to about 5 mg / ml. It may be in contact with ml of said compound of formula I, formula II or formula III.

  [0035] According to another embodiment, a gem-difluorination of general formula I as described above for enhancing engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells or both in a subject in need of transplantation There is provided the use of a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a C-glycopeptide compound or a compound of general formula I as described above.

  [0036] According to another embodiment, a general method as described above for improving insulin secretion function of isolated pancreatic beta cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof Provided is the use of a gem-difluorinated C-glycopeptide compound of formula I, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I as described above. .

  [0037] According to another embodiment, as described above, for protecting isolated pancreatic cells, isolated pancreatic progenitor cells or both from immunosuppressive drug toxicity prior to transplantation in a subject in need thereof. There is provided the use of a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I.

  [0038] According to another embodiment, a general formula I as described above for reducing the inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof. Use of a gem-difluorinated C-glycopeptide compound, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I is provided.

  [0039] The isolated pancreatic cell can be an isolated α cell, isolated β cell, isolated δ cell, isolated γ cell, ε cell, or a combination thereof, and the isolated pancreatic cell is an isolated β cell It is preferable to obtain.

  [0040] The immunosuppressive drug can be one of daclizumab, sirolimus, tacrolimus, cyclosporine, or combinations thereof.

  [0041] The subject can be a human subject.

  [0042] The isolated pancreatic cells, isolated pancreatic progenitor cells, or both can be isolated from a living donor, a cadaver donor, or a combination thereof.

  [0043] The compound of general formula I as described above may be a compound of formula II as described above and / or a compound of formula III as described above.

  [0044] The isolated pancreatic cells, isolated pancreatic progenitor cells or both are about 0.01 mg / ml to about 5 mg / ml of the compound of Formula I, Formula II or Formula III, or about 1 mg / ml to about 5 mg / ml. It may be in contact with ml of said compound of formula I, formula II or formula III.

  [0045] According to another embodiment of the general formula I as described above for use in enhancing the engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells or both in a subject in need of transplantation Pharmaceutically acceptable bases, acid addition salts, hydrates or solvates of gem-difluorinated C-glycopeptide compounds or compounds of general formula I as described above are provided.

  [0046] According to another embodiment, the above, for use in improving the insulin secretion function of isolated pancreatic beta cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof A pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a general formula I gem-difluorinated C-glycopeptide compound as described above or a compound of general formula I as described above Is done.

  [0047] According to another embodiment, for use in protecting isolated pancreatic cells, isolated pancreatic progenitor cells or both from immunosuppressive drug toxicity prior to transplantation in a subject in need thereof. A gem-difluorinated C-glycopeptide compound of general formula I as described above, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I as described above. Provided.

  [0048] According to another embodiment, as described above, for use in reducing the inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof A pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of general formula I or a compound of general formula I as described above is provided. .

  [0049] The isolated pancreatic cell can be an isolated α cell, isolated β cell, isolated δ cell, isolated γ cell, ε cell, or a combination thereof, and the isolated pancreatic cell is an isolated β cell It is preferable to obtain.

  [0050] The immunosuppressive drug can be one of daclizumab, sirolimus, tacrolimus, cyclosporine, or combinations thereof.

  [0051] The subject may be a human subject.

  [0052] Isolated pancreatic cells, isolated pancreatic progenitor cells, or both can be isolated from a living donor, a cadaver donor, or a combination thereof.

  [0053] A compound of general formula I as described above may be a compound of formula II as described above and / or a compound of formula III as described above.

  [0054] The isolated pancreatic cells, isolated pancreatic progenitor cells or both are about 0.01 mg / ml to about 5 mg / ml of the compound of Formula I, Formula II or Formula III, or about 1 mg / ml to about 5 mg / ml. It may be in contact with ml of said compound of formula I, formula II or formula III.

  [0055] The following terms are defined as follows:

  [0056] As used herein, the term "composition" includes a product that includes a specific amount of a specific component and any product that results directly or indirectly from a combination of a specific amount of a specific component. Is intended. Such terms relating to a pharmaceutical composition or other general composition include the active ingredient (s) and the product comprising the inert ingredient (s) constituting the carrier, and any two or more Any product that results directly or indirectly from a combination of components, complexation or aggregation, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components Is intended to be included. Accordingly, the pharmaceutical compositions of the present invention or other general compositions include any composition made by mixing a compound of the present invention and a pharmaceutically acceptable carrier. “Pharmaceutically acceptable” or “acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Means that.

  [0057] The term "pancreatic cell", "isolated pancreatic cell", "islet cell" or "isolated islet cell" refers to an organism isolated by known protocols and / or as described herein below. Alternatively, it is intended to mean cells derived from the islets of Langerhans from the pancreas from cadaveric donors and cells of pancreatic origin grown in vivo, ex vivo and / or in vitro. The cells of the islets of Langerhans produce the hormone glucagon, produce α cells equivalent to about 15-20% of the islet cells, hormone insulin and amylin, β cells equivalent to about 65-80% of the islet cells, the hormone somatostatin Δ cells, which represent approximately 3-10% of the islet cells, PP cells (also known as γ cells) that produce the hormone pancreatic polypeptide (3-5% of the islet cells), and the hormone ghrelin Produced and contains ε cells representing <1% of islet cells.

  [0058] The terms "pancreatic beta cell" and "isolated pancreatic beta cell" refer to cells derived from the pancreas from living or cadaver donors isolated by known protocols and / or as described herein below, And is intended to mean beta cells of pancreatic origin grown in vivo, ex vivo and / or in vitro.

  [0059] The terms "pancreatic progenitor" and "isolated pancreatic progenitor" refer to embryonic stem cells (human or other origin) that have differentiated or differentiated into pancreatic progenitor cells either in vivo, ex vivo or in vitro, or by known protocols. Is intended to mean cells from any suitable source, such as Isolated pancreatic progenitor cells may become pancreatic β cells through further differentiation in vivo, ex vivo or in vitro, either naturally or by treatment using known protocols. For example, isolated pancreatic progenitor cells can be obtained in vitro by a differentiation protocol and further differentiated into pancreatic β cells in vitro by a differentiation protocol. Alternatively, isolated pancreatic progenitor cells can be obtained in vitro by a differentiation protocol and further differentiated into pancreatic β cells in vivo after implantation / transplantation into a patient in need of transplantation.

  [0060] "Alkyl" and other groups with the prefix "alk" such as alkoxy and alkanoyl may be straight or branched, and combinations thereof, unless otherwise defined for the carbon chain Means carbon chain. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like. Where a certain number of carbon atoms is allowed, for example C3-10, the term alkyl also includes cycloalkyl groups and combinations of straight or branched alkyl chains combined with cycloalkyl structures. If the number of carbon atoms is not specified, C1-6 are intended.

  [0061] "Cycloalkyl" is a subset of alkyl and means a saturated carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Unless stated otherwise, cycloalkyl groups are generally monocyclic. Unless otherwise defined, cycloalkyl groups are saturated.

  [0062] The term "alkoxy" has the specified number of carbon atoms (eg, C1-6 alkoxy) or any number within this range [ie, methoxy (MeO-), ethoxy, isopropoxy, etc.]. Refers to straight or branched alkoxide.

  [0063] The term "alkylthio" has the specified number of carbon atoms (eg, C1-6 alkylthio) or any number within this range [ie, methylthio (MeS-), ethylthio, isopropylthio, etc.]. Refers to linear or branched alkyl sulfide.

  [0064] The term "alkylamino" has the specified number of carbon atoms (eg, C1-6 alkylamino) or any number within this range [ie, methylamino, ethylamino, isopropylamino, t- Linear or branched alkylamine such as butylamino].

[0065] The term "alkylsulfonyl" is the number of carbon atoms is not specified (e.g., Cl to 6 alkylsulfonyl), or any number within this range [i.e., methylsulfonyl (MeSO 2 ^_-), ethylsulfonyl, Linear or branched alkylsulfone such as isopropylsulfonyl].

[0066] The term "alkylsulfinyl" has the specified number of carbon atoms (eg, C _1-6 alkylsulfinyl) or any number within this range [ie, methylsulfinyl (MeSO-), ethylsulfinyl, Straight chain or branched alkyl sulfoxides such as isopropyl sulfinyl and the like.

[0067] The term "alkyloxycarbonyl" is the number of carbon atoms is not specified (e.g., C _{1 to 6} alkyloxycarbonyl), or any number [i.e., methyloxycarbonyl within this range (MeOCO ^-), Ethyloxycarbonyl or butyloxycarbonyl] of the carboxylic acid derivative of the present invention.

  [0068] "Aryl" means a monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryls are monocyclic or bicyclic 6 to 10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.

[0069] "Heterocyclyl" is a saturated or unsaturated non-aromatic ring containing at least one heteroatom selected from O, S and N, and further comprising oxidized forms of sulfur, ie SO and SO ₂ Refers to the ring system. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran. , Dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxoazetidin-1-yl 1,2,4-oxadiazin-5 (6H) -one-3-yl and the like.

  [0070] "Heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N. Thus, heteroaryl includes heteroaryl fused to other types of rings such as aryl, cycloalkyl and non-aromatic heterocycles. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl (especially 1,3,4-oxadiazol-2-yl and 1,2,4-oxadiazole-3- Yl), thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, Isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, i Benzyl furanyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and the like. For heterocyclyl and heteroaryl groups, rings and ring systems containing from 3 to 15 atoms are included, forming 1 to 3 rings.

[0071] "Halogen" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. When halogen is substituted with an alkyl or alkoxy group, fluorine is most preferred (eg CF ₃ O and CF ₃ CH ₂ O).

  [0072] Before describing the present invention in detail, a number of terms are defined. As used herein, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

  [0073] Terms such as "preferably", "generally" and "typically" are intended to limit the scope of the claimed invention or to which particular features are claimed. It should be noted that it is not used herein to imply that it is critical, essential, or even important to the structure or function of Rather, these terms are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the present invention.

  [0074] For purposes of describing and defining the present invention, the term “substantially” is used herein to refer to an inherent defect that may result from any quantitative comparison, value, measurement, or other representation. Note that this is used to express the degree of certainty. The term “substantially” is also used herein to describe the extent to which a quantitative expression can vary from the stated criteria without causing a change in the basic function of the subject matter in question. Is done.

  [0075] The features and advantages of the subject matter herein will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying drawings. As will be realized, all of the disclosure and claimed subject matter may be modified in various respects without departing from the scope of the claims. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive, and the full scope of the subject matter is set forth in the appended claims.

FIG. 6 illustrates the use of AAGP ™ to enhance human beta cell health. (A) β islet cell recovery rate after 24 hours with and without AAGP ™ (n = 6 per group); (B) After 24 hours with and without AAGP ™ β islet cell viability (measured with Syto® green / EB) (n = 6 per group); and (CD) glucose-stimulated insulin release with and without AAGP ™ (group 1) N = 3). FIG. 3 illustrates the use of AAGP ™ to protect healthy islets of human β islet cells from tacrolimus (Tac) toxicity. (A) Recovery rate of β islet cells after Tac exposure with and without AAGP ™ (n = 6 per group), (BD) Tac with and without AAGP ™ Β-islet viability after exposure (measured in Syto® green / EB) (n = 6 per group); and (EF) glucose after Tac exposure with and without AAGP ™ Stimulated insulin release (n = 6 per group). FIG. 3 illustrates the use of AAGP ™ to improve transplant outcome. (AD) Graft function after 24 hours with and without AAGP ™ (n = 4 and 5 respectively), (EF) 24 hours with and without AAGP ™ Percentage of normoglycemia 60 days after transplantation of β islet cells with and without (G) AAGP ™ treatment with later graft function (glucose tolerance test) (n = 4 and 5) . FIG. 6 illustrates in vitro evaluation of human islets in cultures with and without AAGP ™ supplementation. (A) Difference in islet recovery rate after 24 hours of culture (p = 0.02). (B) Functional evaluation with perfusion curves comparing glucose stimulated insulin secretion (GSIS). (C) Difference in area under the curve corresponding to the perfusion curve. Data points represent mean ± SEM, n = 3, * P <0.05, *** p <0.001 and *** p <0.0001. FIG. 4 illustrates in vitro evaluation of human islets in cultures with and without AAGP ™ supplementation and tacrolimus exposure. (A) Difference in islet recovery rate after culture and tacrolimus exposure. (B) Functional evaluation with perfusion curves comparing glucose stimulated insulin secretion (GSIS) for different culture conditions. (C) Difference in area under the curve corresponding to the perfusion curve. Data points represent mean ± SEM, n = 6, ** p <0.01 and *** p <0.001. (A) Exemplified increased extracellular reactive oxygen species (ROS) in human islets exposed to tacrolimus without AAGP ™. Oxidative stress was measured by the fold increase in extracellular ROS analyzed with the Acidan Luminogen PS-3 assay (n = 3). After washing AAGP ™ and tacrolimus from the medium, the islets were kept for an additional 3 days. GSIS static assay and intracellular insulin content were measured for different groups on day 3 (Tac present) and day 7 (no Tac). (B) The stimulation index (SI) of the Tac + group was significantly reduced on day 3 compared to Tac + AAGP ™. The SI on day 7 was similar and functional recovery was seen when Tac no longer existed. Despite changes in function, there was no significant change in the intracellular content of insulin measured at baseline (C) and on days 3 and 7 (D). Data points represent the mean ± SEM in triplicate from two different preparations. FIG. 6 illustrates that the effect of AAGP ™ is not the result of direct drug inhibition of tacrolimus. (AC) Direct drug inhibition was assessed using allogeneic mixed lymphocyte reaction (MLR). The results showed a significant decrease in T cell proliferation in the presence of tacrolimus, AAGP ™, and a combination of both, thus demonstrating no direct inhibition of tacrolimus by AAGP ™. Data points represent mean ± SEM, n = 6, *** p <0.001 and *** p <0.0001. FIG. 5 illustrates that acute exposure to tacrolimus does not affect the intracellular content of calcium but decreases exocytosis. Islet calcium concentration remains unchanged despite experimental intervention. (A) Comparative intracellular calcium concentration and (B) Cumulative capacitance of Tac + when compared with the rest of the group and their corresponding decrease in area under the curve (C) Corresponding area under the curve (two different preparations N = 10-16 pancreatic islets). Capacitance measurements were performed to functionally identify the difference in exocytosis (D), thereby showing a significant difference in the exocytosis intermediate group. Data points represent the mean ± SEM of 3 groups with n = 100 islets per group from 2 isolations. It is a figure which illustrates the pro-inflammatory cytokine and chemokine which are acutely expressed after transplantation (24 hours). IL-1β (A), IL-6 (B), TNF (C) and keratinocyte chemokine (KC) (D) concentrations were measured locally on the graft by homogenization. IL-1β, IL-6 and keratinocyte chemokine (KC) concentrations were significantly lower in engrafted islets pretreated with AAGP ™. Cytokines were measured against the graft locally by homogenization (normalized per gram of tissue, n = 3). Data points represent mean ± SEM for pg / mL, normalized per gram of tissue, n = 3, *** p <0.001, *** p <0.0001. It is a figure which illustrates the apoptosis measured acutely 24 hours after transplantation. (A) Representative slide showing multiple staining for insulin (red), TUNEL (green) and nucleus (blue). (B) The percentage of TUNEL positive cells was measured and resulted in significantly higher in the Tac + group. (C) Higher cell mortality in the Tac + group was also confirmed by the concentration of cleaved caspase-3 locally expressed in the graft after homogenization. Results are expressed as an increase in fold change over naive kidney tissue. Results are expressed as an increase in fold change over naive kidney tissue. Percentage of TUNEL positive cells in different study groups as an expression of apoptosis measured acutely after transplantation. Data points represent mean ± SEM adjusted per gram of tissue, n = 3, * p <0.05, ** p <0.01 and *** p <0.0001. FIG. 6 illustrates graft function after transplantation in immunodeficient mice that received a transplant of minimal human islet mass (approximately 1000 IEQ). Islets were pretreated appropriately with AAGP ™ and tacrolimus. (A) Pooled blood glucose profile demonstrating long-term graft function (60 days). The dotted line shows the graft collection nephrectomy on day 60. (B) Intraperitoneal glucose tolerance test (IPGTT) to assess metabolic response after glucose bolus administration. (C) Insulin content of the removed graft 60 days after transplantation as an indicator of residual islet mass. Data points are mean ± SEM adjusted per gram of tissue (Tac−n = 6, Tac + n = 3 and Tac + AAGP ™ n = 7), * p <0.05, ** p <0.01 and *** represents p <0.001. (D) and (E) Graft function after transplantation in mice receiving isogenic transplant (about 500 IEQ) islet transplantation. AAGP ™ was added to the culture medium 1 hour prior to transplantation and tacrolimus was administered at a continuous dose of 1 mg / kg / day via a subcutaneous osmotic pump (embedded during the same procedure). (D) Pooled blood glucose profile of animals over 40 days with clear dysfunction on Tac + islets during the presence of Tac. The vertical dotted line indicates the discontinuation of tacrolimus treatment and marks the slow recovery of the Tac + graft. A horizontal continuous line with y = 11 indicates the limit of normoglycemia. Graft recovery nephrectomy was performed again on day 30. (D) and (E) Graft function after transplantation in mice receiving isogenic transplant (about 500 IEQ) islet transplantation. AAGP ™ was added to the culture medium 1 hour prior to transplantation and tacrolimus was administered at a continuous dose of 1 mg / kg / day via a subcutaneous osmotic pump (embedded during the same procedure). (E) Mean time to euglycemia after transplantation showing Tac + AAGP ™ mice that reverse diabetes earlier (p <0.001, log rank, Mantel-cox test). (F) and (G) Finally, the glucose tolerance test showed a significant difference in graft response to Tac + when mice were administered tacrolimus (7 days) and when the recipient had no CNI. These differences were not observed in the Tac + AAGP ™ group. (F) and (G) Finally, the glucose tolerance test showed a significant difference in graft response to Tac + when mice were administered tacrolimus (7 days) and when the recipient had no CNI. These differences were not observed in the Tac + AAGP ™ group.

[Detailed description]
[0087] Beta cell transplantation is the transplantation of isolated beta islet cells from a donor pancreas into another human. Beta cell transplantation is an experimental treatment for type 1 diabetes. When transplanted, islet β cells begin to produce insulin and actively regulate glucose levels in the blood.

  [0088] Islet is usually infused into the patient's liver. If the cells are not from the same genetic donor, the patient's body recognizes the cells as foreign and, like all transplant rejections, the immune system begins to attack the cells. To prevent this, immunosuppressive drugs are used. Although significant progress has been made in the field of islet transplantation, there are still many obstacles that hinder the widespread application of islet transplantation. Two of the most important limitations are the current lack of means to prevent islet rejection and the limited supply of beta islet cells for transplantation. Current immunosuppressive regimens can prevent beta islet cell failure for months to years, but the drugs used in these treatments are expensive and may increase the risk of certain malignancies and opportunistic infections . In addition, although somewhat ironic, the most commonly used drugs [including daclizumab (Zenapax ™), sirolimus (Rapamune ™), cyclosporine and tacrolimus (Prograf ™) are It is also known to impair normal β islet cell function and / or insulin action.

［式中、
Ｎは、１〜５の整数であり、
Ｒ^４ ＝ Ｈ、ＡＡ_１又はＡＡ_１−ＡＡ_２であり、
Ｒ^５ ＝ ＯＨ、ＡＡ_１又はＡＡ_１−ＡＡ_２であり、
ＡＡ_１及びＡＡ_２は、独立して、非極性側鎖を有するアミノ酸を表し、
Ｒ^１、Ｒ^２、Ｒ^３は、独立した基であり、ここで、Ｒ^１、Ｒ^２及びＲ^３のうちの２つは、Ｈ、ＣＨ_３、ＣＨ_２Ｐｈ、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ（ＣＨ_３）_２又はＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_３から選択され、Ｒ^１、Ｒ^２、Ｒ^３のうちの残りは、

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−グリコシド基又はＣＨ_２−ＯＧＰであり、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^１ ＝ Ｒ^２ ＝ Ｈ、ＣＨ_３、ＣＨ_２Ｐｈ、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ（ＣＨ_３）_２又はＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_３である場合、
Ｒ^３ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−グリコシド基又はＣＨ_２−ＯＧＰであり、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^１ ＝ Ｒ^３ ＝ Ｈ、ＣＨ_３、ＣＨ_２Ｐｈ、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ（ＣＨ_３）_２又はＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_３である場合、
Ｒ^２ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−グリコシド基又はＣＨ_２−ＯＧＰであり、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^２ ＝ Ｒ^３ ＝ Ｈ、ＣＨ_３、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ（ＣＨ_３）_２又はＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_３である場合、
Ｒ^１ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−グリコシド基又はＣＨ_２−ＯＧＰであり、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］である］
のｇｅｍ−ジフルオロ化Ｃ−グリコペプチド化合物、又は一般式Ｉの化合物の薬学的に許容される、塩基、酸付加塩、水和物若しくは溶媒和物と接触させるステップを含む方法が開示される。 [0089] In a first embodiment, an in vitro method for enhancing engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells or both,
a) Prior to transplantation in a subject in need of transplantation, the isolated pancreatic cells, isolated pancreatic progenitor cells or both may be represented by the general formula I:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
A method comprising the step of contacting with a gem-difluorinated C-glycopeptide compound, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I is disclosed.

[0090] According to a second embodiment, an in vitro method for improving the insulin secretion function of isolated pancreatic beta cells prior to transplantation in a subject in need thereof, comprising:
a) An isolated pancreatic beta cell is obtained from a gem-difluorinated C-glycopeptide compound of general formula I or a pharmaceutically acceptable base, acid addition salt, hydrate of a compound of general formula I as described above Alternatively, a method comprising the step of contacting with a solvate is disclosed.

[0091] According to a third, an in vitro method for protecting isolated pancreatic cells, isolated pancreatic progenitor cells or both from the toxicity of an immunosuppressive drug prior to transplantation in a subject in need of transplantation comprising:
a) an isolated pancreatic cell, an isolated pancreatic progenitor cell or both of a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base of a compound of general formula I as described above, Disclosed is a method comprising contacting with an acid addition salt, hydrate or solvate.

[0092] According to a fourth embodiment, an in vitro method for reducing the inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need of transplantation comprising:
a) an isolated pancreatic cell, an isolated pancreatic progenitor cell or both of a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base of a compound of general formula I as described above, Disclosed is a method comprising contacting with an acid addition salt, hydrate or solvate.

[0093] According to a fourth embodiment, a method of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells or both into a subject in need of transplantation, comprising:
a) an isolated pancreatic cell, an isolated pancreatic progenitor cell or both of a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base of a compound of general formula I as described above, Contacting with an acid addition salt, hydrate or solvate;
b) transplanting the treated isolated pancreatic cells of step a) into said subject in need of transplantation.

  [0094] According to one embodiment, the transplantation method of the present invention may further comprise the step a ′) prior to step a), ie a ′) isolating pancreatic cells, pancreatic progenitor cells or both. .

  [0095] According to another embodiment, the method of transplantation of the present invention comprises an immunosuppressive agent for the isolated pancreatic cells, isolated pancreatic progenitor cells or both of step b '): step a) prior to step b). The method may further include contacting with.

  [0096] In embodiments, the transplantation procedure can be performed according to any known and appropriate transplantation procedure, as well as future transplantation procedures that are suitably compatible with the cell types of the present invention. According to one embodiment, the transplantation procedure may be the “Edmonton Protocol”. The islet cell transplant procedure known as the “Edmonton Protocol” involves the transplantation of cadaver islet cells into the patient's hepatic portal vein. Due to the allogeneic nature of transplantation, immunosuppression is provided by the use of calcineurin inhibitors such as tacrolimus. There is a post-transplant period during the engraftment process where the transplanted cells are avascular and under severe stress, and engraftment failure is prone during this period. Other sites for transplantation have been used including subrenal and subcutaneous. According to embodiments, for transplantation of islet or β-progenitor cells, the main transplant site is still the portal vein because a large number of cells are required to achieve the desired effect.

  [0097] According to another embodiment, in the methods of the present invention, the isolated pancreatic cells are isolated α cells, isolated β cells, isolated δ cells, isolated γ cells, ε cells, or combinations thereof. It is possible that the isolated pancreatic cell is preferably an isolated β cell.

  [0098] In the methods of the invention described above, the immunosuppressive drug can be one of daclizumab, sirolimus, tacrolimus, cyclosporine, or combinations thereof.

  [0099] According to embodiments, the subject can be a human subject and the isolated pancreatic cells can be isolated from a living donor, a cadaver donor, or a combination thereof.

［式中、
Ｎは、１〜５の整数であり、
Ｒ^１、Ｒ^２、Ｒ^３は、独立した基であり、ここで、Ｒ^１、Ｒ^２及びＲ^３のうちの２つは、Ｈ、ＣＨ_３から選択され、Ｒ^１、Ｒ^２及びＲ^３のうちの残りは、

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−ＯＧＰから選択され、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’、ＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^１ ＝ Ｒ^２ ＝ Ｈ又はＣＨ_３である場合、
Ｒ^３ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＨ_２−ＯＧＰから選択され、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’、ＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^１ ＝ Ｒ^３ ＝ Ｈ又はＣＨ_３である場合、
Ｒ^２ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ ＝ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’、ＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、Ｂｎ、トシレート、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ又はＣＨ_２−ＯＧＰから選択され、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子Ｈ、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］
であり、
Ｒ^２ ＝ Ｒ^３ ＝ Ｈ又はＣＨ_３である場合、
Ｒ^１ ＝

［式中、
ｎは、３〜４の整数であり、
Ｙ、Ｙ’は、独立した基であり、
ここで、Ｙ、Ｙ’ Ｈ、ＯＲ、Ｎ_３、ＮＲ’Ｒ’’又はＳＲ’’’であり、
ここで、Ｒ ＝ Ｈ、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基であり、
Ｒ’、Ｒ’’は、独立して＝ Ｈ、アルキル、アリル、ベンジル、トシレート基、Ｃ（＝Ｏ）−アルキル又はＣ（＝Ｏ）−Ｂｎであり、
Ｒ’’’ ＝ Ｈ、アルキル又はアセテート基であり、
Ｒ^６は、Ｈ、ＣＨ_３、ＣＨ_２ＯＨ又はＣＨ_２−ＯＧＰから選択され、ここで、ＧＰは、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から選択される保護基であり、
Ｒ^７ ＝ ＯＨ、ＯＧＰ’、ＮＨ_２、Ｎ_３、ＮＨＧＰ’又はＮＧＰ’ＧＰ’’であり、ここで、ＧＰ’及びＧＰ’’は、アルキル、ベンジル、トリメチルシリル、ｔｅｒｔ−ブチルジメチルシリル、ｔｅｒｔ−ブチルジフェニルシリル又はアセテート基から独立して選択され、
Ｒ^８は、水素原子、又は遊離アルコール官能基若しくは保護されたアルコール官能基である］である］
の化合物であってもよい。 [00100] According to one embodiment, the gem-difluorinated C-glycopeptide compound of general formula I is of general formula II:

[Where:
N is an integer of 1 to 5,
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are selected from H, CH ₃ and R ¹ , R ² and R ³ The rest of the

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H or CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H or CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″, SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, Bn, tosylate, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H or CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom, or a free alcohol function or a protected alcohol function]]
It may be a compound of

の化合物である。 [00102] According to another embodiment, a preferred gem-difluorinated C-glycopeptide compound of general formula I is of formula III, also named AAGP ™:

It is a compound of this.

  [00103] According to another embodiment, isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the methods of the invention are disclosed.

[00104] According to another embodiment, a method of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells, or both into a subject in need of transplantation, comprising:
Disclosed is a method comprising the step of transplanting an isolated pancreatic cell, isolated pancreatic progenitor cell or both prepared according to the method of the present invention into said subject in need of transplantation.

[00105] According to another embodiment, a method of treating diabetes comprising:
Disclosed is a method comprising the step of transplanting an isolated pancreatic cell, isolated pancreatic progenitor cell or both prepared according to the method of the present invention into said subject in need of transplantation.

  [00106] According to another embodiment, the isolated pancreatic cells can be isolated α cells, isolated β cells, isolated δ cells, isolated γ cells, ε cells, or a combination thereof, and the isolated pancreas The cell is preferably an isolated β cell.

  [00107] According to another embodiment, the use of isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the methods of the invention for transplantation into a subject in need of transplantation is disclosed. .

  [00108] According to another embodiment, there is disclosed the use of isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the methods of the invention for the treatment of diabetes in a subject in need of transplantation. The

  [00109] According to another embodiment, an isolated pancreatic cell, isolated pancreatic progenitor cell or both prepared by the method of the present invention for transplantation into a subject in need of transplantation is disclosed.

  [00110] According to another embodiment, the isolated pancreatic cells can be isolated α cells, isolated β cells, isolated δ cells, isolated γ cells, ε cells, or a combination thereof, and the isolated pancreas The cell is preferably an isolated β cell.

  [00111] According to another embodiment, a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, acid addition salt, water of a compound of general formula I as described above Disclosed are isolated pancreatic cells, isolated pancreatic progenitor cells, or both in contact with a solvate or solvate.

  [00112] According to another embodiment, a gem-difluorination of general formula I as described above for enhancing engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells or both in a subject in need of transplantation Disclosed is the use of a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a C-glycopeptide compound, or a compound of general formula I as described above.

  [00113] According to another embodiment, the general as described above for improving the insulin secretion function of isolated pancreatic beta cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof Disclosed is the use of a gem-difluorinated C-glycopeptide compound of formula I, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I as described above. .

  [00114] According to another embodiment, as described above for protecting isolated pancreatic cells, isolated pancreatic progenitor cells or both from immunosuppressive drug toxicity prior to transplantation in a subject in need thereof Disclosed is the use of a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I as described above. The

  [00115] According to another embodiment, a general formula I as described above for reducing the inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof. Use of a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound, or a compound of general formula I as described above, is disclosed.

  [00116] According to another embodiment of the general formula I as described above for use in enhancing the engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells or both in a subject in need of transplantation Disclosed are pharmaceutically acceptable bases, acid addition salts, hydrates or solvates of gem-difluorinated C-glycopeptide compounds, or compounds of general formula I as described above.

  [00117] According to another embodiment, the above, for use in improving the insulin secretion function of isolated pancreatic beta cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof Disclosed are gem-difluorinated C-glycopeptide compounds of general formula I as described above, or pharmaceutically acceptable bases, acid addition salts, hydrates or solvates of compounds of general formula I as described above. Is done.

  [00118] According to another embodiment, for use in protecting isolated pancreatic cells, isolated pancreatic progenitor cells or both from immunosuppressive drug toxicity prior to transplantation in a subject in need thereof. A gem-difluorinated C-glycopeptide compound of general formula I as described above, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I as described above. Disclosed.

  [00119] According to another embodiment, as described above for use in reducing the inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof Disclosed is the use of a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I as described above. Is done.

  [00120] According to another embodiment, the compound of formula I may be a compound of formula II and / or a compound of formula III.

  [00121] According to another embodiment, the isolated pancreatic cells, isolated pancreatic progenitor cells or both are about 0.01 mg / ml to about 5 mg / ml of said compound of formula I, formula II or formula III, or It may be contacted with about 1 mg / ml to about 5 mg / ml of said compound of formula I, formula II or formula III.

  [00122] In the use of the invention described above, the immunosuppressive drug can be one of daclizumab, sirolimus, tacrolimus, cyclosporine or combinations thereof.

  [00123] According to the uses and compounds described above, the subject can be a human subject and the isolated pancreatic cells can be isolated from a living donor, a cadaver donor, or a combination thereof.

  [00124] According to another embodiment, the isolated pancreatic cells can be isolated alpha cells, isolated beta cells, isolated delta cells, isolated gamma cells, epsilon cells, or a combination thereof, and the isolated pancreas The cell is preferably an isolated β cell.

  [00125] The present invention includes compounds as indicated, and (where possible) individual diastereomers, enantiomers and epimers of the compounds, and mixtures of the diastereomers and / or enantiomers including racemic mixtures. Including. Although the specific stereochemistry disclosed herein is preferred, other stereoisomers including diastereomers, enantiomers, epimers, and mixtures thereof may also be useful. Inactive or less active diastereoisomers and enantiomers are useful for scientific research on targets and / or activation mechanisms.

  [00126] The compounds disclosed herein are used in a pharmaceutical composition comprising (a) compound (s) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier. be able to. The compounds can be used in pharmaceutical compositions comprising one or more other active pharmaceutical ingredients. The compounds can also be used in pharmaceutical compositions where the compound of formula I, II or III or a pharmaceutically acceptable salt thereof is the only active ingredient.

  [00127] Compounds of structural formula I, structural formula II, and / or structural formula III may contain one or more asymmetric centers, and thus racemates and racemic mixtures, single enantiomers, diastereomers Can occur as a mixture of isomers and individual diastereomers. The present invention is meant to encompass all such isomeric forms of the compounds of structural formula I, structural formula II and / or structural formula III.

  [00128] Compounds of structural formula I, structural formula II and / or structural formula III may be chiral, for example, by fractional crystallization from a suitable solvent, such as methanol or ethyl acetate or mixtures thereof, or using an optically active stationary phase. Chromatography can separate the individual diastereoisomers of the compound. The absolute stereochemistry can be determined by X-ray crystal structure analysis of a crystal product or a crystal intermediate derivatized with a reagent containing an asymmetric center whose absolute configuration is known as necessary.

  [00129] Alternatively, any stereoisomer of a compound of general structural formula I, structural formula II and / or structural formula III is stereospecific using an optically pure starting material or reagent of known absolute configuration. It can be obtained by synthesis.

  [00130] If desired, racemic mixtures of the compounds can be separated so that the individual enantiomers are isolated. Separation involves coupling a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of individual diastereomers by standard methods such as fractional crystallization or chromatography, etc. Can be carried out by methods well known in the art. The coupling reaction is often the formation of a salt using an enantiomerically pure acid or base. The diastereomeric derivatives can then be converted to the pure enantiomers by cleaving the added chiral residue. Racemic mixtures of compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

  [00131] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

  [00132] Some of the compounds described herein may exist as tautomers, with different points of attachment of hydrogen associated with one or more double bond shifts. For example, ketones and their enol forms are keto-enol tautomers. The individual tautomers and mixtures thereof are encompassed with the compounds of the present invention.

[00133] In the compounds of general formula I, formula II and / or formula III, the atoms may exhibit their natural isotopic abundance, or one or more of the atoms have the same atomic number However, a specific isotope having an atomic mass or mass number different from the atomic mass or mass number mainly found in nature may be artificially enriched. The present invention is meant to include all suitable isotopic variations of the compounds of general formula I, formula II and / or formula III. For example, different isotope forms of hydrogen (H) include protium ( ¹ H) and deuterium ( ² H). Protium is the main hydrogen isotope found in nature. Concentrating deuterium can provide certain therapeutic benefits such as increased in vivo half-life or reduced dosage requirements, or compounds useful as standards for characterization of biological samples. Can be provided. Isotope-enriched compounds within the general formula I, formula II and / or formula III can be prepared without undue experimentation by conventional techniques well known to those skilled in the art.

Salts and formulations
[00134] As used herein, references to compounds of structural formula I, formula II and / or formula III also include pharmaceutically acceptable salts and free compounds or pharmaceutically acceptable salts thereof. It will be understood that salts that are not pharmaceutically acceptable when used as precursors to the salts made or in other synthetic operations are also included. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed by the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of the invention that are generally prepared by reacting the free base with a suitable organic or inorganic acid. . Representative salts of the basic compound of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, disulfide Tartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, edetic acid, edicylate, estrate, esylate, fumarate, glucate , Gluconate, glutamate, hexyl resorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate Acid salt, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucinate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, salt Acid salt, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, basic acetate, succinate Acid salts, tannic acid salts, tartrate salts, theocrate salts, tosylate salts, triethiodides and valerate salts. Further, when the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium , Salts derived from inorganic bases, including magnesium, manganous, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N, N -Dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, Examples include salts of piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

  [00135] Also, when a carboxylic acid (-COOH) or alcohol group is present in the compounds of the present invention, an ester of a pharmaceutically acceptable carboxylic acid derivative such as methyl, ethyl or pivaloyloxymethyl, or acetyl, Acyl derivatives of alcohols such as pivaloyl, benzoyl and aminoacyl can be used. Included are esters and acyl groups known in the art for modifying solubility or hydrolysis properties for use as sustained release or prodrug formulations.

  [00136] Solvates, particularly hydrates, of compounds of structural formula I, formula II and / or formula III are likewise included in the invention.

  [00137] According to one embodiment, the compounds of structural formula I, formula II and / or formula III may be included in various formulations for use as pharmaceuticals.

  [00138] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; dispersants or wetting agents are naturally occurring phosphatides From, for example, lecithin, or a condensation product of an alkylene oxide and a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide and a long chain aliphatic alcohol, such as heptadecaethyleneoxycetanol, or ethylene oxide and a fatty acid and hexitol. Condensation products with derived partial esters, such as polyoxyethylene sorbitol monooleate, or parts derived from ethylene oxide and fatty acids and hexitol anhydrides Condensation products of esters may be, for example polyethylene sorbitan monooleate. Aqueous suspensions contain one or more preservatives such as ethyl or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose, Saccharin or aspartame may also be included.

  [00139] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those mentioned above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

  [00140] Dispersible powders or granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. To do. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

  [00141] The pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifiers include naturally occurring phosphatides such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as Polyoxyethylene sorbitan monooleate may be used. The emulsion may also contain sweetening and flavoring agents.

  [00142] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

  [00143] According to one embodiment, the cells are isolated using methods known in the art for their preparation. For example, cells are isolated from a donor (living or cadaveric donor) using a mixture of enzymes such as collagenase I and collagenase II, thermolysin, non-Clostridial neutral protease or other enzymes used for such purposes. can do. The isolated cells can then be cultured under normal tissue culture conditions in standard tissue culture flasks.

  [00144] According to one embodiment, the cells, pancreatic progenitor cells or both are about 0.01 mg / ml to about 5 mg / ml; or about 0.1 mg / ml to about 5 mg / ml; or about 0.5 mg / ml. or about 1 mg / ml to about 5 mg / ml; or about 3 mg / ml to about 5 mg / ml; or about 0.01 mg / ml to about 3 mg / ml, or about 0.1 mg / ml About 3 mg / ml, or about 0.5 mg / ml to about 3 mg / ml, or about 1 mg / ml to about 3 mg / ml, or about 0.01 mg / ml to about 1 mg / ml; or about 0.1 mg / ml About 1 mg / ml; or about 0.5 mg / ml to about 1 mg / ml; or about 0.01 mg / ml to about 0.5 mg / ml; or about 0.1 mg / ml to about 0.5 mg / ml; 0.01 mg / ml to about 0.1 mg / ml; or about It can be treated with various concentrations of 3 mg / ml gem-difluorinated C-glycopeptide compounds of general formula I-preferably compounds of formula II, most preferably compounds of formula III. According to embodiments, the above amounts are considered to be therapeutically effective for the purposes of the present invention.

  [00145] According to another embodiment, the cells are contacted with the gem-difluorinated C-glycopeptide compound for a time sufficient to provide an improvement in cell viability and viability. According to embodiments, sufficient time is from about 12 hours to 120 hours, or from about 12 hours to about 96 hours, or from about 12 hours to about 72 hours, or from about 12 hours to about 48 hours, or from about 12 hours to It can be about 24 hours, or about 120 hours, or about 96 hours, or about 72 hours, or about 48 hours, or about 24 hours, or about 12 hours.

  [00146] In another embodiment, a cell preparation prepared according to the methods of the invention in a pharmaceutically acceptable carrier is disclosed. According to one embodiment, the cell preparation can be used for the preparation of a medicament for cell transplantation. According to another embodiment, the cell preparation can be used for cell transplantation.

  [00147] In another embodiment, a method of transplantation comprising the step of transplanting a cell preparation of the invention into a subject in need of transplantation is disclosed. The subject can be a mammal, preferably a human.

  [00148] The invention will be more readily understood by reference to the following examples, which are provided to illustrate the invention rather than to limit the scope of the invention.

Example 1
Use of AAGP ™ to enhance human beta cell health
Initial characterization
experimental method
[00149] Research grade human islet preparations are divided into the following groups and cultured for 24 hours:
[00150] 1) AAGP ™ supplemented islet cells; and
[00151] 2) Control group (non-supplemented islet cells).

[00152] Islets are cultured at a density of 200 IE / mL in a humidified atmosphere of 37 ° C 95% air and 5% CO ₂ using standard tissue culture flasks. The AAGP ™ concentration is 3 mg / mL. Several tests are performed on the first day after islet isolation, including islet restoration, membrane integrity viability staining (Syto® EB) and glucose stimulated insulin release. The results are shown in FIGS.

Example 2
Use of AAGP ™ to protect human β cells from tacrolimus toxicity
experimental method
[00153] Research-grade human islet preparations are cultured for 48 hours in the following groups:
[00154] 1) β islet cells treated without tacrolimus (Tac-);
[00155] 2) beta islet cells treated with tacrolimus (Tac +); and
[00156] 3) Treated with tacrolimus (Tac +) + AAGP ™ supplemented β islet cells.

  [00157] After 48 hours, tacrolimus (10 ng / L) was added to Groups 2 and 3.

[00158] The islets are cultured at a density of 200 IE / mL in a humidified atmosphere of 37% 95% air and 5% CO ₂ using standard tissue culture flasks. The AAGP ™ concentration is 3 mg / mL. Several tests are performed after islet isolation at D1, including islet restoration, membrane integrity viability staining (Syto EB) and glucose stimulated insulin release. The results are shown in FIGS.

Example 3
Use of anti-aging glycopeptides to improve transplant outcomes
experimental method
[00159] Two research grade human islet preparations are cultured for 24 hours in the following groups:
[00160] 1) AAGP ™ + supplemented islet cells; and
[00161] 2) Control group (non-supplemented islet)

[00162] Islets are cultured at a density of 200 IE / mL in a humidified atmosphere of 37% 95% air and 5% CO ₂ using standard tissue culture flasks. The AAGP ™ concentration is 3 mg / mL. 24 hours later, subrenal capsule islet transplantation is performed in immunodeficient mice (Rag1) with minimal islet mass (approximately 1000 IEQ) to assess the efficacy of transplantation (n = 4 and 5, control and AAGP ™, respectively) ). The results are shown in FIGS.

Conclusion
[00163] The AAGP ™ formulation is not toxic to human islet cells.
[00164] AAGP ™ appears to increase islet survival in culture.
[00165] AAGP ™ protects islets exposed to tacrolimus in vitro.
[00166] In transplant studies with minimal islet mass, AAGP ™ appeared to provide benefits to transplanted islets, but no conclusions were drawn.

Example 4
Islet isolation and purification
[00167] In all experiments, human islets are used. Islets are isolated from dead donors at a clinical good manufacturing practice (GMP) facility within the University of Alberta's clinical islet transplant program. Briefly, the pancreas is obtained from a multi-organized dead donor and either a histidine-tryptophan-ketoglutarate (HTK, Custodiol. Metapharm, Brandford, ON, Canada) solution or a static storage solution (SPS-1, Itasca, IL, USA). The glands are then expanded with Liberase MTF C / T GMP (Roche Diagnostics GmbH, Manheim, Germany), supplemented with CIzyme collagenase and CIzyme thermolysin (Vitacyte LLP, Indianapolis, Ind., USA) and digested with Ricor. Free islets are identified by using a cell processor (model 91, or 91, weL, iL, Spring, Spring, 2010). Further purification with CO, USA).

Example 5
In vitro evaluation
[00168] Islets are counted with dithizone staining (final concentration 3 mg / mL, Sigma-Aldrich, ON, Canada) using optical graticule at the beginning and end of culture. The total number of islets is converted to islet equivalent (IEQ) (standardized to a diameter of 150 μm) (Isletation for clinical translation, Shahidul. M (ed.), The islets of Langerhans, New York, United Yr: 20 , Cell translation 2000; 9 (3): 409-414).

[00169] For initial characterization, islets from three different preparations were divided into two groups, 10% fetal calf serum, L-glutamine (100 mg / 100%) at 37 ° C, 5% CO ₂ and saturated humidity. l), cultured in medium supplemented with penicillin (112 kU / l), streptomycin (112 mg / l) and HEPES (25 mmol / l); pH 7.4) with NaOH (CMRL-1066, Mediatech, Manassas, VA, USA) . One group is also supplemented with 3 mg / mL, AAGP ™ (ProtoKinetrix), a synthetic analog of AFP. AAGP ™ is highly soluble in all media and has proven to be more stable while retaining high bioactivity properties comparable to natural AFP. The other group served as a control.

  [00170] After 24 hours of culture, islets are assessed for recovery, viability and function. The recovery rate is calculated as the percentage of viable islets after 24 hours of culture compared to the initial count for each condition. Viability is assessed using a fluorescent membrane integrity assay using counterstained cytogreen / ethidium bromide (Cedarlane Laboratories, Burlington, ON, and Sigma-Aldrich, ON) (Islet isolation for clinical transplantation. (Eds.), The islets of Langerhans, New York: Springer, 2010; Rancolli A, et al., Cell translation 2000; 9 (3): 409-414; Ricordi C, et al., Acta diabetica 19: 27; And Barnett MJ et al., Cell t ansplantation 2004; 13 (5): 481~488).

  [00171] Islet secretion function is assessed by monitoring in vitro insulin secretion profiles during continuous glucose stimulation as described by Cabrera et al., Cell translation 2008; 16 (10): 1039-1048. This in vitro perfusion assay is a form of continuous glucose-stimulated insulin secretion (GSIS) test that stresses islets in alternating euglycemic and hyperglycemic environments to model physiological islet responses. The supernatant of the perfusion assay is collected and insulin levels are determined using a commercially available ELISA kit (Insulin ELISA kit, Mercodia Inc., Pittsburgh, PA, USA). Results are normalized as 100 IEQ and expressed as fold change in insulin secretion compared to a low (2.8 mMol) glucose stimulated baseline.

Example 6
Tacrolimus toxicity
[00172] The cytoprotective ability of AAGP ™ is evaluated against tacrolimus-induced toxicity (Johnson JD et al., Cell translation 2009; 18 (8): 833-845). Islets from six different research grade human islet preparations are divided into three groups: one AAGP ™ supplemented group and two non-supplemented control groups. Islets are kept in similar culture conditions for 24 hours, followed by addition of tacrolimus (Prograf, Astellas Pharma Canada Inc., Markham, ON, Canada) in one of the AAGP ™ and control groups (positive control) To do. Tacrolimus is added to the culture medium at a clinically relevant dose of 10 ng / mL and all groups are further cultured for 24 hours followed by perfusion to determine pro-inflammatory cytokines, oxidative stress and apoptosis. The result is a figure? ? Shown in

Example 7
Proinflammatory cytokines and chemokines
[00173] After 24 hours exposure to tacrolimus, samples from all groups of culture media were frozen and related cytokines and chemokines (IFN-γ, IL-1β, IL-6, IL-10, IL-12, keratinocytes) Derived chemokines (KC) and TNF-α) from a multi-spot human pro-inflammatory 7-Plex ultra-sensitive kit (Multi-Spot Ultra-Sensitive kit) (Meso Scale DiscoveryGa, registered trademark) MD, USA) and analyzed with a SECTOR ™ Imager (Meso Scale Discovery®, Gaithersburg, MD, USA). Results are expressed as absolute values (pg / mL) and a single CMRL culture medium is used as a control for comparison.

Example 8
ROS analysis
[00174] Reactions in culture medium using frozen samples from all groups and using the Acidan Lumigen ™ PS-3 assay (Amershan ECL Plus kit, Fisher Scientific Inc., Ottawa, ON, Canada) Reactive oxygen species (ROS) is determined (18). In this assay, Acridan Lumigen ™ PS-3 is excited by reactive oxygen and nitrogen species (RNS) in the presence of hydrogen peroxide, causing chemiluminescence at 430 nm. Media samples are snap frozen in liquid nitrogen and stored until the assay is performed. A single CMRL culture medium was used as a control and the results are expressed as an increase in fold change compared to the control medium.

Example 9
Apoptosis analysis
[00175] Apoptosis is measured in all groups using a truncated caspase-3 spectrophotometric assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. All determinations are made with 100 IEQ normalization groups and their corresponding culture media.

  [00176] A frozen media sample is used to determine the increase in cleaved caspase-3 using a spectrophotometric assay (EMD Millipore ™, Billerica, MA, USA). Again, a single CMRL culture medium with additive and no cells was used as a control, and the results are expressed as an increase in fold change compared to the control medium.

  [00177] For TUNEL staining (DeadEnd ™ Apoptosis Detection System, Promega, Madison, WI), islets are fixed in formalin, processed, and embedded in paraffin. Co-staining is performed to identify grafts (insulin), apoptotic cells and all nuclei present in the field. Apoptosis is quantified by the percentage of positive TUNEL stained areas using ImageJ software.

Example 10
Transplant
[00178] 8-12 week old immunodeficient mice (B6.129S7-Rag1 ^tm1Mom ) were obtained from Jackson Laboratory (Bar Harbor, ME, USA) and raised under specific pathogen removal conditions with free access to food and water. To do. Animals are cared for in accordance with Canadian Animal Care Institute guidelines and are ethically approved by the Animal Welfare Committee at the University of Alberta.

  [00179] Diabetes is chemically induced by intraperitoneal injection of streptozotocin (STZ, Sigma-Aldrich, ON, Canada) at a dose of 180 mg / kg. The animal is determined to be diabetic after two consecutive blood glucose measurements record ≧ 18 mmol / L.

  [00180] Ten animals per group received approximately 1,000 IEQ of human islets transplanted under the left kidney capsule as previously described (19).

Example 11
Transplant nephrectomy at 24 hours
[00181] Nephrectomy is performed on 3 mice per group, euthanized 24 hours after transplantation, and an acute determination of pro-inflammatory cytokines, cleaved caspase-3 and TUNEL in the graft area is performed. In all cases, islet grafts are excised from the kidney, weighed, snap frozen in liquid nitrogen and stored at -80 ° C. The tissue samples were then lysed with 1 ml lysis buffer (0.15 M NaCl, 1 mM Tris-HCL, 0.1% SDS, 0.1% Triton X-100, 20 mM sodium deoxycholate, 5 mM EDTA) per 200 mg tissue. To dissolve. The lysate was then repeatedly homogenized on ice (PowerGen, Fisher Scientific, ON, Canada) twice for 30 seconds and sonicated with 10 rapid pulses on ice (VirSonic, VirTis, NY). USA). Cell debris was pelleted by centrifugation at 14,000 rpm for 10 minutes at 4 ° C., and the resulting supernatant was collected and 10 μl protease inhibitor cocktail (Sigma-Aldrich Canada Co., Oakville per ml lysate). , ON, Canada) into a microcentrifuge tube containing (1: 100).

  [00182] Graft samples are assayed for pro-inflammatory cytokine / chemokine, caspase-3 and TUNEL staining (using corresponding mouse kit) as described above. All decisions are adjusted per gram of tissue.

Example 12
Long-term graft function
[00183] Using a portable glucometer (One Touch Ultra 2, LifeScan, Canada), non-fasting blood glucose is monitored three times per week for 60 days with the remaining 7 mice per group. When the reading is less than 11.3 mmol / L for two consecutive times, it is defined as normoglycemia.

  [00184] An intraperitoneal glucose tolerance test (IPGTT) is performed 60 days after transplantation to assess the ability of islets to respond to a glucose bolus (3 g / kg) after an overnight fast. Blood glucose levels are monitored at baseline (time points 0, 15, 30, 60, 90 and 120 minutes after injection). All results are compared to the blood glucose profile of naive control mice.

  [00185] Recovery nephrectomy is performed on all animals on day 65 to demonstrate graft-dependent normoglycemia. Nonfasting blood glucose levels are recorded over 1 week after nephrectomy. Similarly, the native pancreas is excised at the terminal end, fixed in 10% formalin, and analyzed by immunohistochemistry to confirm the absence of mouse insulin staining, thus excluding the residual or regeneration of native pancreatic β-cell function. .

  [00186] The stored grafts are then processed as described above, and residual insulin content is determined using a human insulin ELISA as a measure of viable islets.

Example 13
Statistical analysis
[00187] Data are expressed as mean ± standard error of the mean (SEM). The area under the curve is calculated for GSIS and IPGTT and the difference between groups is analyzed with one-way ANOVA and Tukey's post-hoc test. A p value <0.05 is considered significant and all analyzes are performed using GraphPad Prism (GraphPad Software, La Jolla, CA, USA).

Example 14
AAGP ™ enhances islet preservation in culture
[00188] Isolated human islets from three different preparations are cultured for 24 hours in medium supplemented with or without AAGP ™ to assess islet mass conservation and functional changes. After 24 hours of culture, islets are counted, resulting in significant differences in islet recovery. There is no difference in cell viability according to the membrane integrity assay (data not shown), but more viable islets are observed in the AAGP ™ supplemented group (76.62 ± 7.4%) Vs. 50.63 ± 6.2%, p = 0.029) (FIG. 4A).

  [00189] When comparing the in vitro function (GSIS) of these two groups, a significant increase is observed in insulin secretion from AAGP ™ supplemented islets during the second secretion phase, as shown in the perfusion curve (P <0.001) (FIG. 4B). The resulting area under the curve confirmed an overall increased insulin release from AAGP ™ supplemented islets (AUC, 149.5 ± 0.5 vs. 75.5 ± 0.5, p <0. (001) (FIG. 4C).

Example 15
AAGP ™ effectively protects islets from tacrolimus-related damage
[00190] Based on the known diabetes-inducing effects of calcineurin inhibitors (CNI), particularly tacrolimus, a toxic islet assay is performed to assess the cytoprotective capacity of AAGP ™. Again, isolated human islets from 6 different preparations are cultured for 24 hours in medium supplemented with or without AAGP ™ followed by 24 hours exposure to a clinically relevant dose of 10 ng / mL tacrolimus. To test the cytoprotective effect of AAGP ™, islets are cultured in the presence of culture medium alone (Tac-), tacrolimus alone (Tac +) or AAGP ™ with tacrolimus (Tac + AAGP ™). After a defined culture period, all groups are characterized for in vitro survival, viability, function and oxidative stress.

  [00191] Supplementing with AAGP ™ led to increased survival of islets after culture despite the presence of the known β-cytotoxic drug, tacrolimus. The Tac + AAGP ™ group showed similar recovery rates as islets not exposed to tacrolimus. However, survival is significantly increased when compared to the Tac + group (67.65% vs 31.55%, p <0.001) (FIG. 5A). Although there was no difference in cell viability by membrane integrity staining (data not shown), GSIS perfusion resulted in a significant difference in insulin secretion between Tac + and Tac + AAGP ™. The AAGP ™ supplement group showed a biphasic insulin response to glucose similar to control islets that were not exposed to tacrolimus. Conversely, the Tac + group resulted in a highly impaired response (AUC: Tac− vs. Tac +, 158.8 vs. 8.22, p <0.001; Tac− vs. Tac + AAGP ™, 158.8). Vs. 129.3, p = 0.231 .; Tac + vs. Tac + AAGP ™, 8.22 vs. 129.3, p = 0.003) (FIGS. 5B, 5C).

  [00192] The potential impact of AAGP ™ on the oxidative stress that occurs in human islets while being cultured and exposed to tacrolimus is measured by a fold increase in extracellular ROS. Twenty-four hours after exposure to tacrolimus, media samples are taken from each group and analyzed with an Acidan Luminogen PS-3 assay. As expected, oxidative stress occurred in all samples, but exposure to tacrolimus resulted in a significant increase in ROS (FIG. 6A). However, this phenomenon is ameliorated in the presence of AAGP ™ (p = 0.012).

  [00193] Isolated human islets from six different preparations were cultured for 24 hours in medium supplemented with or without AAGP ™ and supplemented with tacrolimus for an additional 24 hours. After a total culture period of 48 hours, all groups were characterized for in vitro survival, viability, function and oxidative stress.

  [00194] As expected, oxidative stress occurred in all samples, but exposure to tacrolimus resulted in a significant increase in ROS (Figure 6A). However, this phenomenon was ameliorated in the presence of AAGP ™ (n = 3, p <0.05).

  [00195] Similar experimental conditions were reproduced (human islets cultured with and without AAGP ™ and exposed to tacrolimus). Approximately 100 IEQ aliquots on day 3, each corresponding s-GSIS assay Groups and simultaneous intracellular insulin content were collected. The islets were then extensively washed to remove tacrolimus and left to incubate for an additional 4 days, with sampling and comparative testing repeated on day 7.

  [00196] Similar to the initial assessment, the Tac + group showed markedly impaired insulin secretion on day 3, which was not observed in the Tac + AAGP ™ series (stimulus index 1.4 vs. 9.7, p <0.01, FIG. 6B). However, this decrease in insulin secretion is transient, with the intergroup difference disappearing by day 7 when tacrolimus is no longer present, and the expected overall decreased islet activity at the end of the culture period. Has been adjusted. Despite differences in insulin secretion profiles, intracellular insulin content was stable and comparable across all groups, indicating that there was no change in insulin biosynthesis in β cells ( 6C and 6D).

Example 16
AAGP ™ does not inhibit the immunosuppressive ability of tacrolimus
[00197] To confirm that AAGP ™ did not inhibit tacrolimus T cell proliferation inhibition, a mixed lymphocyte reaction using mouse splenocytes was performed. The assay measures the T cell proliferative response by the level of CFSE staining. As expected, T cell proliferation was significantly reduced in the presence of tacrolimus compared to the IgG control (n = 4, p <0.001). The proliferation of CD8 + and CD4 + positive T cells was also significantly reduced in the presence of tacrolimus alone or in combination with AAGP ™ (n = 4, p <0.001 in each case). However, there was no significant decrease in T cell proliferation when exposed to a single AAGP ™ (FIG. 7).

Example 17
Effect of tacrolimus on intracellular calcium content and exocytosis in islets.
[00198] Various electrophysiological studies were conducted on human islets to characterize CNI-related damage and its avoidance to reveal potential mechanisms of action for AAGP ™. No significant difference in calcium influx between groups was found (FIGS. 8A, 8C), indicating that a possible mechanism of action is further downstream of the insulin pathway.

  [00199] As an indirect indicator of exocytosis during high glucose stimulation, supplemental capacitance studies were performed in these same conditions. The results show that the cumulative capacitance of the Tac + group is reduced compared to the other groups and that the area under the curve is significantly lower when compared to the Tac + AAGP ™ group (AUC: 39. 08 vs. 68.01, p <0.01) (FIGS. 8B, 8D).

Example 18
AAGP ™ ameliorates the inflammatory response immediately after transplantation
[00200] Further in vivo studies will be performed to supplement the inventors' in vitro findings. Using the same study group (Tac−, Tac + and Tac + AAGP ™), minimal mass (approximately 1,000 IEQ) islet transplantation is performed on chemically induced diabetic immunodeficient mice (n = 10 per group). ). To measure the potential effect of AAGP ™ on the local post-transplant inflammatory response, homogenized harvested grafts (24 hours post-transplant) from 3 animals in each group for pro-inflammatory cytokines and chemokines Determine characteristics.

  [00201] Acute levels of IL-1β are increased in all groups relative to that of naïve mice. Although the level of the Tac + group was significantly higher, the addition of AAGP ™ significantly attenuated this cytokine excretion (17.81 vs 4.94 pg / mL / g-tissue, p <0.001) (FIG. 9A). A similar effect is observed when measuring IL-6 levels, resulting in a significant decrease in the presence of AAGP ™ (147.8 vs 54.4 pg / mL / g-tissue, p < 0.001) (FIG. 9B). However, there was no discernable difference in TNF-α levels between the groups exposed to tacrolimus (1.63 vs. 1.34 pg / mL / g-tissue) (FIG. 9C).

  [00202] Among chemokines measured acutely after transplantation, KC secretion, which is involved in neutrophil recruitment, is associated with major secretion changes. Similar to IL-1β and IL-6, KC is significantly overexpressed in the Tac + group and again decreases significantly in the presence of AAGP ™ (9.79 vs 3.58 pg / mL / g-tissue). , P <0.001) (FIG. 9D). When comparing in vitro cytokine and chemokine expression, no significant differences were observed between groups (data not shown).

Example 19
AAGP ™ reduces islet apoptosis after transplantation
[00203] Acutely removed grafts (24 hours after transplantation) are also analyzed for apoptosis within the graft. The increase in fold change in the level of cleaved caspase-3 is determined relative to the basal level in the naïve mouse kidney. There was a significant increase in the level of caspase-3 in the Tac + group relative to Tac + AAGP ™, essentially showing a level very similar to that of islets not exposed to tacrolimus (3.14 vs. 1). .46, p <0.001) (FIG. 10B). The remaining graft sections are further analyzed for apoptosis using the TUNEL assay, showing consistent results that the percentage of TUNEL positive cells is dominant in the Tac + group when compared to Tac + AAGP ™ and controls. (53.3% vs. 24.0% vs. 14.9%, p <0.023) (FIGS. 10A, 10C).

Example 20
In vivo AAGP ™ supplemented islet function improved despite tacrolimus exposure
[00204] The remaining transplanted mice (n = 7 per group) are followed up to 60 days after transplantation to determine the effectiveness of transplantation and to evaluate long-term graft function. Blood glucose is monitored regularly to determine the percentage of normoglycemia. As expected in this marginal islet mass model, delayed survival is observed. Blood glucose improved over time in the Tac− and Tac + AAGP ™ groups, as opposed to the Tac + group, where all mice remained hyperglycemic until the end of day 60 (FIG. 11A).

  [00205] IPGTT was performed on study groups 60 days after transplantation to assess islet transplantation function. Both Tac− and Tac + AAGP ™ groups responded appropriately, but Tac + remained highly diabetic until 120 minutes (AUC: Tac− vs. Tac + AAGP ™, 92.63 vs. 91.20, p. = 0.095; Tac- vs naive, 92.63 vs 71.43, p = 0.434; Tac + AAGP ™ vs naive, 91.20 vs 71.43, p = 0.423, and Tac + vs Tac + AAGP ( Trademark), 149.8 vs. 91.2, p = 0.021) (FIG. 11B).

  [00206] A graft harvest nephrectomy is performed on day 60 to demonstrate that the transplanted islets are the only cause of the observed normoglycemia. All mice returned to their previous diabetic state, which was also confirmed by weak insulin staining of their native pancreas (data not shown).

  [00207] At the time of graft recovery, insulin content is determined as an indicator of residual islet mass 60 days after transplantation. FIG. 11C shows significant differences between groups with significant insulin content reduction in grafts exposed to tacrolimus. Again, the presence of AAGP ™ is beneficial for islet protection despite exposure to tacrolimus (Tac + vs. Tac + AAGP ™, 30.86 vs. 100.8 ng / mL, p <0.01).

  [00208] To further support these findings, transplantation experiments were performed in a syngeneic diabetic mouse transplant model with continuous treatment with tacrolimus to resemble clinical practice. Similar to the in vitro setting, transplanted islets exposed to tacrolimus (in this case at a higher concentration to account for differences in mouse tacrolimus metabolism) effectively secrete insulin and return the animal to normoglycemic status I couldn't. However, the presence of AAGP ™ allowed the islets to function normally, and the period during which normoglycemia was achieved was similar to the control group (FIGS. 11D, 11E, p <0.001).

  [00209] These findings are also observed when comparing the initial intraperitoneal glucose tolerance test (IPGTT) under tacrolimus treatment, a regulation that is clearly ineffective in the Tac + group when compared to the other groups. (FIG. 11F, AUC: 101 vs. 54.69 and 59.26, p <0.01)

  [00210] Upon discontinuation of tacrolimus treatment, the islets regained their normal function and the animals became normoglycemic, similar to their study controls. In repeated IPGTT at the end point (30 days), the difference disappeared and all animals displayed similar behavior when challenged with a high glucose bolus (FIG. 11G).

Consideration
[00211] It is demonstrated herein that the addition of AAGP ™, a potent AFP, to islet culture media significantly protects human islet survival and in vitro function. Furthermore, AAGP ™ protected human islets from tacrolimus-related damage, along with engraftment and in vivo benefits including markers of acute inflammation, apoptosis and long-term graft function.

  [00212] Even though islet culture provides considerable flexibility in clinical transplantation, 14-20% islet loss is routinely observed due to multiple factors from the donor and isolation process (Kin T et al., Transplant international: official journal of the European Society for Organ Transplantation 2008; 21 (11): 1029-1035). When the culture medium is supplemented with AAGP ™, significant improvements in islet recovery and function are consistently observed with various human islet preparations.

  [00213] The mechanism by which AFP protects cells under hypothermia remains difficult to understand. Various authors have reported that the role of membrane stabilization of these molecules to prevent uncontrolled ion migration that occurs at low temperatures reduces the risk of cell destruction (22). Given that irregular membrane permeation can occur as a result of hypoxia and ischemia-reperfusion even at ambient conditions, it is quite possible that this mechanism can be applied to our experimental design (Karlé). C, et al., American journal of physiology Lung cellular and molecular physology 2004; 286 (6): L1154-1160; Weir EK et al, Cardiovascular reserch; circuity physology 2013; 304 (1): H94-103).

  [00214] Tacrolimus is an immunosuppressant that is widely used in the field of islet transplantation and is an important factor that is routinely used to reduce the risk of acute, chronic rejection and recurrent autoimmunity. (Shapiro AM et al., The New England journal of medicine 2000; 343 (4): 230-238). However, this and other long-term use of CNI has been associated with side effects, mainly nephrotoxicity and post-transplantation diabetes (Chand DH et al., Pediatric translation 2001; 5 (1): 32-36). In fact, damage related to both tacrolimus and cyclosporine has been reported in islets and inhibition of calcineurin / activated T cell nuclear factor (NFAT) signaling (Oetjen E, et al., Molecular pharmacology 2003; 63 (6): 1289-1295), insulin gene suppression (Hernandez-Fisac I, et al., American journal of translation 2007; 7 (11): 2455-2462), mitochondrial arrest (Rostambeigi N, et al., Transplantation 2011: 156: 916: 236: 916) ) And reduced post-transplant angiogenesis (Nishimura R et al., PloSone 2013; 8 (4): e56799). It is characterized by several mechanisms.

  [00215] As shown herein, the in vitro presence of clinically relevant doses of tacrolimus was significantly detrimental to human islets by reducing survival in culture and suppressing insulin secretion, but the AAGP ™ Addition clearly protected human islets from this toxicity.

[00216] Islets are highly sensitive to hypoxia resulting from donation through culture and intraportal transplantation. This phenomenon is mainly due to the high oxygen demand and size of the pancreatic islets, which causes a harmful pO ₂ gradient to be generated depending on the seeding density during culture (Papas KK et al., Transplantation processeds 2005; 37 ( 8): 3412-3414). The islets are susceptible to oxidative stress due to reduced antioxidant capacity (Sklavos MM et al. Diabetes 2010; 59 (7): 1731-1738). These factors contribute to islet loss during culture and after transplantation. The findings indicate an increase in oxidative stress in the Tac + group, as demonstrated by an increase in extracellular ROS in the culture medium.

  [00217] In vivo experiments are performed to supplement all in vitro findings and to correlate AAGP ™ supplementation with early inflammation, cell death, engraftment and long-term efficacy. Graft characterization of acutely euthanized mice showed clear evidence for the anti-inflammatory potential of the study compounds. AAGP ™ -supplemented islets showed a significant decrease in IL-1β and IL-6 expression with decreased secretion of keratinocyte chemokines despite exposure to tacrolimus in culture. These cytokines and chemokines, along with TNF-α, are important players in post-transplant inflammatory responses and subsequent adaptive immune activation (Kanak MA ™ et al., International Journal of Endocrinology 2014).

  [00218] Tacrolimus has also been associated with increased cell death in islets (Johnson JD et al., Cell translation 2009; 18 (8): 833-845). In this experiment, the fold change of cleaved caspase-3 in the graft was measured as an index of apoptosis, and then the same graft was subjected to TUNEL staining. The results consistently showed a decrease in apoptosis in the AAGP ™ supplemented group at levels similar to naive human islets not exposed to tacrolimus.

  [00219] Glucose tolerance tests performed again at the end of the study showed similar glucose normalization rates for the Tac- and Tac + AAGP ™ groups, which are not significantly different from naive mice. These results correlated with residual graft mass expressed as final insulin content. On the other hand, the deleterious effects of tacrolimus exposure without AAGP ™ appear to be sufficient to damage the islet engraftment, blood glucose does not decrease after challenge with a glucose bolus, glucose Normalization was not possible.

  [00220] To make our experiments more clinically relevant, a new in vivo syngeneic mouse transplantation model was performed with tacrolimus as a continuous treatment with a subcutaneous osmotic pump. It was observed that transplanted islet dysfunction occurred immediately after the start of CNI administration and lasted for the entire treatment period (7 days). When immunosuppression was stopped, graft function gradually normalized, and all groups were comparable by the end point.

  [00221] However, islets treated with AAGP ™ did not appear to be affected by the presence of high doses of CNI and functioned as well as the control group.

  [00222] These findings support previous in vitro experiments showing the temporary and deleterious effects of tacrolimus that can be reversed when the drug is removed. Clearly, discontinuation of tacrolimus may not be possible in current clinical settings. Further regulatory toxicity studies are required before administering AAGP ™ molecules to patients, but perhaps the solution may be to treat these individuals with AAGP ™ simultaneously to prolong the cytoprotective effect. unknown.

  [00223] Despite the overwhelming evidence of the beneficial effects of AAGP ™ on pancreatic islets, a clear mechanism of action or mechanistic process to avoid tacrolimus toxicity is known for this drug Absent. During these experiments, it was demonstrated that there was no direct pharmacological inhibition of tacrolimus in the presence of AAGP ™ by performing an MLR assay without AAGP ™ interference in the anti-proliferative effect of tacrolimus.

  [00224] Furthermore, neither tacrolimus nor AAGP ™ was found to affect the calcium concentration of islets, an important component of the insulin synthesis-secretion mechanism in β cells. This information supports the recently published evidence (Uchizono Y et al., Endocrinology 2004; 145: 2264-2272) pointing to potential tacrolimus mechanical sites further downstream in the secretory pathway. Indeed, capacitance measurements on islets showed a significant difference between the Tac + group and the TAC + AAGP ™ group. These findings can be interpreted as indicators of exocytosis disorders not observed with Tac + AAGP ™.

  [00225] In conclusion, supplementing human islets with AAGP ™ during culture improves the quality and yield of the final preparation and is converted to improved engraftment in the presence of the islet toxic drug tacrolimus. It was. This approach could potentially improve clinical transplantation as a potential strategy for single donor islet transplantation. The above approach may also open up other promising paths for research in cell, tissue and organ preservation.

  [00226] While preferred embodiments have been described above and illustrated in the accompanying drawings, it will be apparent to those skilled in the art that modifications may be made without departing from the disclosure. Such modifications are considered possible variations that fall within the scope of the present disclosure.

Claims (55)

An in vitro method for enhancing engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells or both,
a) Prior to transplantation in a subject in need of transplantation, the isolated pancreatic cells, isolated pancreatic progenitor cells or both may be represented by the general formula I:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of said gem-difluorinated C-glycopeptide compound, or a compound of general formula I. An in vitro method for improving the insulin secretion function of isolated pancreatic beta cells prior to transplantation in a subject in need thereof, comprising:
a) The isolated pancreatic β-cell is represented by the general formula I:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of said gem-difluorinated C-glycopeptide compound, or a compound of general formula I. An in vitro method for protecting isolated pancreatic cells, isolated pancreatic progenitor cells or both from the toxicity of an immunosuppressive drug prior to transplantation in a subject in need of transplantation, comprising:
a) An isolated pancreatic cell, an isolated pancreatic progenitor cell or both is represented by the general formula I:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of said gem-difluorinated C-glycopeptide compound, or a compound of general formula I. An in vitro method for reducing the inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need of transplantation comprising:
a) An isolated pancreatic cell, an isolated pancreatic progenitor cell or both is represented by the general formula I:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of said gem-difluorinated C-glycopeptide compound, or a compound of general formula I. A method of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells or both into a subject in need of transplantation, comprising:
a) An isolated pancreatic cell, an isolated pancreatic progenitor cell or both is represented by the general formula I:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Contacting with a gem-difluorinated C-glycopeptide compound, or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a compound of general formula I;
b) transplanting the treated isolated pancreatic cells of step a) into said subject in need of transplantation. Step a ′) before step a):
6. The method of claim 5, further comprising: a ') isolating pancreatic cells, pancreatic progenitor cells or both.   The method according to claim 5 or 6, further comprising the step of contacting the isolated pancreatic cells, isolated pancreatic progenitor cells or both of step b ') step a) prior to step b) with an immunosuppressive drug.   The isolated pancreatic cell is any one of claims 1 and 3 to 7, wherein the isolated pancreatic cell is an isolated α cell, isolated β cell, isolated δ cell, isolated γ cell, ε cell, or a combination thereof. the method of.   The method according to any one of claims 1 and 3 to 7, wherein the isolated pancreatic cells are isolated β cells.   8. The method according to any one of claims 3 and 5-7, wherein the immunosuppressive drug is one of daclizumab, sirolimus, tacrolimus, cyclosporine or combinations thereof.   The method of any one of claims 1 to 10, wherein the subject is a human subject.   12. The method according to any one of claims 1 to 11, wherein the isolated pancreatic cells are isolated from a living donor, a cadaver donor, or a combination thereof. The compound of formula I is of formula II:

[Where:
N is an integer of 1 to 5,
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are selected from H, CH ₃ and R ¹ , R ² and R ³ The rest of the

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H or CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H or CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″, SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, Bn, tosylate, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H or CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom, or a free alcohol function or a protected alcohol function]]
The method as described in any one of Claims 1-12 which is a compound of these. Said compound of formula I is of formula III:

The method according to any one of claims 1 to 13, which is a compound of   15. The method of any one of claims 1-14, wherein the step of contacting the isolated pancreatic cells is contact with about 0.01 mg / ml to about 5 mg / ml of the compound of Formula I, Formula II, or Formula III. The method described in 1.   16. The method of claim 15, wherein the step of contacting the isolated pancreatic cell is contact with about 1 mg / ml to about 5 mg / ml of the compound of Formula I, Formula II, or Formula III.   An isolated pancreatic cell, isolated pancreatic progenitor cell, or both, prepared according to the method of any one of claims 1-4. A method of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells or both into a subject in need of transplantation, comprising:
a) transplanting isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the method of any one of claims 1 to 4 into said subject in need of transplantation. A method of treating diabetes,
a) transplanting the isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the method of any one of claims 1 to 4 into a subject in need of transplantation.   Use of isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the method of any one of claims 1 to 4 for transplantation into a subject in need of transplantation.   Use of isolated pancreatic cells, isolated pancreatic progenitor cells or both prepared according to the method of any one of claims 1 to 4 for the treatment of diabetes in a subject in need of transplantation.   An isolated pancreatic cell, isolated pancreatic progenitor cell or both prepared by the method of any one of claims 1 to 4 for transplantation into a subject in need thereof. Formula I:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
An isolated pancreatic cell, single contacted with a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of formula I or a compound of general formula I Isolated pancreatic progenitor cells or both. The compound of formula I is of formula II:

[Where:
N is an integer of 1 to 5,
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are selected from H, CH ₃ and R ¹ , R ² and R ³ The rest of the

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H or CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H or CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″, SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, Bn, tosylate, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H or CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom, or a free alcohol function or a protected alcohol function]]
24. The isolated pancreatic cell, isolated pancreatic progenitor cell, or both of claim 23, wherein Said compound of formula I is of formula III:

25. The isolated pancreatic cell, isolated pancreatic progenitor cell, or both of claim 23 or 24.   The isolated pancreatic cell according to any one of claims 22 to 25, which is an isolated α cell, isolated β cell, isolated δ cell, isolated γ cell, ε cell or a combination thereof.   The isolated pancreatic cell according to any one of claims 22 to 25, which is an isolated β cell.   26. Isolated pancreatic cell, isolated pancreas according to any one of claims 23 to 25, which is in contact with about 0.01 mg / ml to about 5 mg / ml of said compound of formula I, formula II or formula III Progenitor cells or both.   30. The isolated pancreatic cell, isolated pancreatic progenitor cell or both according to claim 28, which is in contact with about 1 mg / ml to about 5 mg / ml of said compound of formula I, formula II or formula III. For enhancing engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells or both in a subject in need of transplantation, the general formula I:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of general formula I: General formula I for improving the insulin secretion function of isolated pancreatic beta cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of general formula I: A general formula I for protecting isolated pancreatic cells, isolated pancreatic progenitor cells or both from immunosuppressive drug toxicity prior to transplantation in a subject in need thereof:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of general formula I: For reducing the inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need of transplantation:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
Or a pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of general formula I:   34. The isolated pancreatic cell according to any one of claims 30, 32 to 33, wherein the isolated pancreatic cell is an isolated α cell, isolated β cell, isolated δ cell, isolated γ cell, ε cell, or a combination thereof. Use of.   34. Use according to any one of claims 30, 32 to 33, wherein the isolated pancreatic cells are isolated beta cells.   35. Use according to claim 32, wherein the immunosuppressive drug is one of daclizumab, sirolimus, tacrolimus, cyclosporine or combinations thereof.   34. Use according to any one of claims 30 to 33, wherein the subject is a human subject.   38. Use according to any one of claims 30 to 37, wherein the isolated pancreatic cells, isolated pancreatic progenitor cells or both are isolated from a living donor, a cadaver donor or a combination thereof. The compound of formula I is of formula II:

[Where:
N is an integer of 1 to 5,
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are selected from H, CH ₃ and R ¹ , R ² and R ³ The rest of the

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H or CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H or CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″, SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, Bn, tosylate, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H or CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom, or a free alcohol function or a protected alcohol function]]
Use according to any one of claims 30 to 38, which is a compound of Said compound of formula I is of formula III:

40. Use according to any one of claims 30 to 39, which is a compound of   4. The step of contacting said isolated pancreatic cell, isolated pancreatic progenitor cell or both is from about 0.01 mg / ml to about 5 mg / ml of said compound of formula I, formula II or formula III. Use according to any one of 30 to 40.   42. The contacting of said isolated pancreatic cell, isolated pancreatic progenitor cell or both with about 1 mg / ml to about 5 mg / ml of said compound of formula I, formula II or formula III. Use of description. General formula I for use in enhancing the engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells or both in a subject in need of transplantation:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
A pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of formula I: General formula I for use in improving the insulin secretion function of isolated pancreatic beta cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
A pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of formula I: A general formula I for use in protecting isolated pancreatic cells, isolated pancreatic progenitor cells or both from the toxicity of immunosuppressive drugs prior to transplantation in a subject in need thereof:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
A pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of formula I: General formula I for use in reducing the inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells or both prior to transplantation in a subject in need thereof:

[Where:
N is an integer of 1 to 5,
R ⁴ = H, AA ₁ or AA ₁ -AA ₂ ,
R ⁵ = OH, AA ₁ or AA ₁ -AA ₂ ;
AA ₁ and AA ₂ independently represent an amino acid having a nonpolar side chain;
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , Selected from CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃ and the rest of R ¹ , R ² , R ³ is

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H, CH ₃ , CH ₂ Ph, CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H, CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ or CH (CH ₃ ) CH ₂ CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is H, CH ₃ , CH ₂ OH, CH ₂ -glycoside group or CH ₂ -OGP, where GP is alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or A protecting group selected from acetate groups;
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]]
A pharmaceutically acceptable base, acid addition salt, hydrate or solvate of a gem-difluorinated C-glycopeptide compound of formula I:   47. The isolated pancreatic cell according to any one of claims 43, 45 to 46, wherein the isolated pancreatic cell is an isolated α cell, isolated β cell, isolated δ cell, isolated γ cell, ε cell, or a combination thereof. Compound.   47. The compound according to any one of claims 43, 45 to 46, wherein the isolated pancreatic cell is an isolated beta cell.   46. The compound of claim 45, wherein the immunosuppressive drug is one of daclizumab, sirolimus, tacrolimus, cyclosporine or combinations thereof.   50. The compound according to any one of claims 43 to 49, wherein the subject is a human subject.   51. The compound of any one of claims 43-50, wherein the isolated pancreatic cell, isolated pancreatic progenitor cell, or both are isolated from a living donor, a cadaver donor, or a combination thereof. The compound of formula I is of formula II:

[Where:
N is an integer of 1 to 5,
R ¹ , R ² , R ³ are independent groups, wherein ^{two of} R ¹ , R ² and R ³ are selected from H, CH ₃ and R ¹ , R ² and R ³ The rest of the

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ² = H or CH ₃
R ³ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH, CH ₂ —OGP, where GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′, NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ¹ = R ³ = H or CH ₃
R ² =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ = H, OR, N ₃ , NR′R ″, SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, Bn, tosylate, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom H, or a free alcohol function or a protected alcohol function]
And
When R ² = R ³ = H or CH ₃
R ¹ =

[Where:
n is an integer of 3 to 4,
Y and Y ′ are independent groups,
Where Y, Y ′ H, OR, N ₃ , NR′R ″ or SR ′ ″,
Where R = H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or an acetate group;
R ′ and R ″ are independently ═H, alkyl, allyl, benzyl, tosylate group, C (═O) -alkyl or C (═O) —Bn;
R ′ ″ = H, an alkyl or acetate group,
R ⁶ is selected from H, CH ₃ , CH ₂ OH or CH ₂ —OGP, wherein GP is selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate groups A protecting group
R ⁷ = OH, OGP ′, NH ₂ , N ₃ , NHGP ′ or NGP′GP ″, where GP ′ and GP ″ are alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert- Independently selected from butyldiphenylsilyl or acetate groups;
R ⁸ is a hydrogen atom, or a free alcohol function or a protected alcohol function]]
52. The compound according to any one of claims 43 to 51, wherein the compound is: Said compound of formula I is of formula III:

52. The compound according to any one of claims 43 to 51, wherein the compound is:   54. The contact of any of claims 43-53, wherein the step of contacting the isolated pancreatic cells is contact with about 0.01 mg / ml to about 5 mg / ml of the compound of formula I, formula II or formula III. Compound described in 1.   55. The step of contacting the isolated pancreatic cell, isolated pancreatic progenitor cell, or both is contact with about 1 mg / ml to about 5 mg / ml of the compound of Formula I, Formula II, or Formula III. The described compound.

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